Abstract:  In this article, we review the experimental data supporting an oncostatic role of melatonin on hormone‐dependent mammary tumors. Beginning with the evidence on the role of estrogens in breast cancer etiology and mammary tumor growth, we summarize the actual therapeutic strategies with estrogens as a target. Additionally, we demonstrate that melatonin fulfills all the requirements to be considered as an antiestrogenic drug which shares properties with drugs of the two main pharmacological groups of substances which interact with the estrogen‐signaling pathways such as: (i) drugs that act through the estrogen receptor interfering with the effects of endogenous estrogens; and (ii) drugs that interfere with the synthesis of estrogens by inhibiting the enzymes controlling the interconversion from their androgenic precursors. Furthermore, melatonin decreases circulating levels of estradiol. These three antiestrogenic mechanisms suggest that melatonin may have an important role in the prevention and treatment of hormone‐dependent mammary cancer.

Melatonin is an indole hormone produced mainly by the pineal gland. We have previously demonstrated that melatonin interferes with estrogen (E₂) signaling in MCF7 cells by impairing estrogen receptor (ER) pathways. Here we present the characterization of its mechanism of action showing that melatonin is a specific inhibitor of E₂-induced ERα-mediated transcription in both estrogen response element- and AP1-containing promoters, whereas ERβ-mediated transactivation is not inhibited or even activated at certain promoters. We show that the sensitivity of MCF-7 cells to melatonin depends on the ERα/ERβ ratio, and ectopic expression of ERβ results in MCF-7 cells becoming insensitive to this hormone. Melatonin acts as a calmodulin antagonist inducing conformational changes in the ERα-calmodulin (CaM) complex, thus impairing the binding of E₂·ERα·CaM complex to DNA and, therefore, preventing ERα-dependent transcription. Moreover the mutant ERα (K302G,K303G), unable to bind calmodulin, becomes insensitive to melatonin. The effect of melatonin is specific since other related indoles neither interact with CaM nor inhibit ERα-mediated transactivation. Interestingly, melatonin does not affect the binding of coactivators to ERα, indicating that melatonin action is different from that of current therapeutic anti-estrogens used in breast cancer therapy. Thus, they target ERα at different levels, representing two independent ways to control ERα activity. It is, therefore, conceivably a synergistic pharmacological effect of melatonin and current anti-estrogen drugs.